When proteins fold the molecules adopt regular, compact shapes (conformations) that are determined by the sequence of amino acid residues along the peptide chain. The precise folded conformation determines the biological properties of the folded protein; it is invariably made up of local sheet, helix, and turn regions, which are short, highly regular locally folded structures. Under vary well-defined conditions, polypeptides, which are short, highly regular locally folded structures. Under vary well-defined conditions, polypeptides, which are short sequences of amino acid residues, can be found to adopt helix, turn, or sheet conformations. These can be sued as models for studying the more complex problem of how proteins themselves fold. During the past project period a new tool, the reporting conformational template (RCT), has been demonstrated in our labs that greatly extends the range of helical small polypeptides and that provides a new and precise means of measuring their stability. During the next project period, the RCT principle will be used to study systematically the properties of helices formed in water by small polypeptides of varying amino acid composition and sequence. From these studies, algorithms will be developed that allow accurate prediction of the stability of a helix formed by any polypeptide sequence. In effect, the part of the protein folding problem that deals with helix formation will have been solved. A second major aim of the project is synthesis of ~superhilical~ amino acids which are not found in nature, but which can be incorporated into natural polypetides to greatly increase their helical stability. When achieved, these aims will provide essential insights into the process by which proteins fold. They will also generate research tools that bioscientists can use to study a large number of medically relevant issues. Helical sections of proteins are involved in recognition steps key to the pathology of human disease states. A helical peptide has been recently shown to mimic the binding of the HIV virus to a human cell in the first step of a cascade that leads to infection. Oncogenes, which regulate the development of many human tumors, are regulated by DNA-protein interactions, which again often involve helix- oligonucleotide interactions. Development of superstable peptide helices should provide an important research tool in understanding and controlling these processes.